PROJECT SUMMARY/ABSTRACT Huntington's Disease (HD) is a movement disorder caused by a single genetic mutation in the Htt gene. Mutation positive individuals can be identified by genetic testing many years before ?manifest? HD, which provides the opportunity for neuroprotective treatments to prevent or delay irreversible brain damage. However, as the symptoms are subtle and cannot be relied on as outcome measures in this ?premanifest? period, there is an urgent need for biomarkers for determining an optimal treatment window, and for evaluating efficacy in thera- peutic trials. Regional brain atrophy can be detected before motor onset in HD, initially found by us, and con- firmed in several multi-center studies. Meanwhile, accumulating evidence indicates that some brain abnormali- ties other than structural changes may present even earlier and may be more sensitive to therapeutic interven- tions. Cerebrovascular abnormalities have been reported in premanifest and early HD, which may occur earlier and progress more rapidly than structural changes. Early detection of such abnormalities would provide a ra- tionale for initiating treatment earlier, and might provide a sensitive means of monitoring effects of treatment in the absence of clinical symptoms. Most previous studies of cerebrovascular abnormalities in HD measured total cerebral blood volume (CBV) and flow (CBF) in the brain, which reflect the sum of signals from the arterial and venous compartments in the microvasculature. However, different types of blood vessels have distinct functions and physiology, and can be affected differentially by the HD pathology. The arterioles are the most actively regulated blood vessels in the microvasculature. We have recently reported significant changes in arteriolar CBV in the brain in premanifest HD patients when regional atrophy was undetectable, and the change in arteriolar CBV was greater than total CBF and brain volumetric changes. In this proposal, we will characterize longitudinal cerebrovascular changes in arteriolar and venous blood vessels using HD mouse models, and determine whether the cerebrovascular measures respond to neuroprotective treatments for HD. Our central hypothesis is that microvascular alterations (most likely arteriolar CBV) can be detected before and may progress faster than structural changes, and such abnormality can be an early and sensitive biomarker for indicating optimal treat- ment period and evaluating efficacy. Aim 1: To identify the spatiotemporal dynamics of cerebrovascular changes in arteriolar and venous blood vessels in HD mouse in both the premanifest and manifest stages, and to de- termine whether the cerebrovascular alterations occur before behavioral deficits and brain atrophy, and progress over time. MRI measures will be validated by histology. Aim 2: To assess whether cerebrovascular measures can be used to indicate optimal treatment window and evaluate efficacy for neuroprotective therapies. Taken together, the proposed studies will advance our understanding of cerebrovascular abnormalities in HD, and identify alterations in specific microvascular compartments and brain regions. The results will provide proof-of-principle for using MRI-based cerebrovascular measures as a potential biomarker in HD.